JP5080989B2 - Imaging of the object of interest - Google Patents

Description

  The present invention relates to the field of imaging. In particular, the present invention relates to an apparatus, arrangement and method for imaging an object of interest, to a method for utilizing particles having an acceptor and / or donor in an apparatus, arrangement or method for imaging an object of interest, and to a computer readable medium. , Relating to program elements.

  There are several methods for diagnostic imaging of body parts. Such techniques include ultrasound imaging and fluorescence imaging. A major challenge in fluorescence imaging within a turbid medium (eg, tissue) is that the spatial resolution is very poor due to strong scattering of excitation and emission fluorescence. Thus, the resolution of the prior art optical fluorescent X-ray tomography is limited.

  Another problem encountered when using light (eg, fluorescence) as an imaging means is that there is no modulation. It is known to reconstruct an image by reconstructing the image resulting from the combination of sound waves and illumination. See the book “Acousto-Optics” by A. Korpel (Marcel Dekker Inc. 1997). In the method described above, the refractive index variation caused by the sound wave is visualized by the effect of the refractive index variation on the incident light. However, the rate variation caused by sound waves is small and the image quality is poor.

Another method that allows for variations in light intensity involves modifying the distance between the partner of the fluorescent donor / acceptor pair. Donor molecules absorb excitation light but do not fluoresce. If the donor is close enough to the acceptor, energy is transferred to the acceptor by so-called fluorescence resonance energy transfer (FRET) or, more generally, by direct dipole-dipole interaction, and the acceptor emits fluorescence. . Thus, the fluorescence intensity depends on the distance between the donor and acceptor. Fluorescence resonance energy transfer (FRET) is a phenomenon that is strongly dependent on the distance between the donor and acceptor (proportional to r- ⁶ ). The transition from a state without energy transfer to a state in which energy transfer is very effective is very sharp, ie high fluorescence modulation can be achieved. FRET has been used in biology applications seeking binding between proteins, or in the study of membrane structure or the study of interactions between membranes. For these purposes, vesicles containing fluorescent donors and / or acceptors of FRET have been developed (Wong and Groves 2002 Proc. Natl. Acad. USA 99, 14147-14152; John et al. 2002 Biophys. J. 83 , 1525-1534; Leidy et al 2001 Biophys. J. 80, 1819-1828).

  Ultrasonic microbubble vesicles with fluorescent groups are known, for example, from US Pat. No. 6,123,923.

  An object of the present invention is to make it possible to image an object of interest with sufficient accuracy.

  To achieve the above object, an apparatus, an arrangement and a method for imaging an object of interest, a method using particles comprising an acceptor and / or a donor, and a computer readable medium comprising the arrangement of the independent claims Providing program elements.

  According to an exemplary embodiment of the present invention, an apparatus for imaging an object of interest is provided. The device is adapted to emit at least two different frequencies of ultrasound on the object of interest and is responsive to absorption of primary electromagnetic radiation and emitted by the object of interest in response to ultrasound. And an electromagnetic radiation detector adapted to detect electromagnetic fluorescence radiation.

  According to another exemplary embodiment of the present invention, there is provided an array for imaging an object of interest having an object of interest and having an apparatus having the above-described configuration for imaging of the object of interest.

  Furthermore, according to another exemplary embodiment of the present invention, emitting at least two different frequencies of ultrasonic waves on the object of interest, in response to absorption of primary electromagnetic radiation, and in response to ultrasonic waves Detecting an electromagnetic fluorescent radiation emitted by the object of interest.

  Furthermore, according to another exemplary embodiment of the present invention, a method of using particles is taught. The particles can attach to the object of interest and emit donors and / or electromagnetic fluorescent radiation adapted to absorb electromagnetic radiation for devices, arrays and methods having the above-described configuration for imaging the object of interest. Has an acceptor.

  Further provided is a computer readable medium storing a computer program for imaging an object of interest adapted to perform the aforementioned method steps when executed by a processor.

  Furthermore, according to another exemplary embodiment of the present invention, there is provided a program element for imaging an object of interest adapted to perform the aforementioned method steps when executed by a processor.

  Imaging of the object of interest according to the present invention can be performed by a computer program (ie, by software), by using one or more special optimization electronics (ie, in hardware), or in a complex form (ie, It can be realized by software components and hardware components.

  The characteristic arrangement according to the invention has the advantage in particular that an imaging system based on the emission of multi-frequency ultrasound to the object of interest is provided, combined with the absorption and fluorescence of electromagnetic radiation by the object of interest. The emission of different frequencies of ultrasound to different parts of the object has the effect that mechanical vibrations of that part of the object of interest are induced at the characteristic frequency. This mechanical vibration frequency modulates the emission characteristics of the portion of the electromagnetic fluorescent radiation. Thus, the mechanical vibration states of different parts of the object of interest are different. This results in different characteristics of the fluorescence emission of the different parts. Since different parts of the object of interest are affected by ultrasound having different frequencies, the fluorescent signals of the aforementioned different parts are appropriately modulated. As a result, frequency analysis of the re-emitted electromagnetic fluorescence emission spectrum makes it possible to distinguish between the fluorescence contributions from different parts of the object. Therefore, spatially resolved reproduction of the physical structure of the object of interest is possible.

  If the material of the object of interest is excited by primary electromagnetic radiation (eg, light from the environment or light source) and if a portion of the object of interest is mechanically vibrated by ultrasound of a different frequency, the object of interest It is possible to detect an electromagnetic fluorescence detection signal obtained by encoding information on the structure of The aforementioned information is included at the ultrasonic modulation frequency and at the intensity of the separate contribution of the measured signal.

  In particular, when ultrasound waves having different frequencies strike different locations on the sample, the optical signal re-emitted in response to the previously absorbed excitation radiation (which can be detected by a photodetector) is of interest. It has an overlaid frequency component that can be assigned to different positions of the object. This makes it possible to clearly recalculate the structure of the object of interest.

  One or more donor / acceptor pairs can be provided on the object of interest. The donor can be adapted to absorb the excitation light and the acceptor can be equipped to interact with the donor so that the donor transfers energy to the acceptor so that the acceptor can emit fluorescence. . This movement may depend on the current distance between the donor and acceptor. If the distance is sufficiently small, energy transfer can be turned on, and if the distance is sufficiently large, energy transfer can be turned off. If the distance between the donor and acceptor is modulated by vibrations induced by ultrasonic sound, the re-emitted fluorescence signal is modulated accordingly. Therefore, the detection signal pattern is characteristically corrected by the frequency of the ultrasonic wave hitting the corresponding part of the object. As a result, the (three-dimensional) structure of the target object can be reconstructed by the frequency pattern detected by the detector.

  The imaging system according to the present invention enables high-speed parallel imaging using a probe (for example, an optical type) that can be driven by ultrasonic waves. Therefore, high resolution (optical) fluorescence imaging is possible. According to an exemplary embodiment of the present invention, microbubbles are attached to an object of interest. The microbubbles emit fluorescence only during exposure to the ultrasound focus. Thus, in effect, the size of the ultrasound focus determines the resolution of the imaging. Since the multi-frequency transducer according to the present invention can emit ultrasonic waves having different frequencies, it is essential according to the present invention that a specific field of view must be scanned point by point. Thus, the time required for the measurement procedure is considerably shortened. In accordance with the present invention, an imaging method is disclosed that allows parallel imaging processing, thereby resulting in a significant reduction in acquisition time.

  One aspect according to the present invention is to simultaneously apply an array of ultrasonic focal points to the field of view (FOV) and use frequency encoding (to attribute the resulting optical signal from the field of view to the focal point itself). This is possible. This is because the optical fluorescence signal from a specific ultrasonic focus is modulated by the frequency of the ultrasonic field at the location of this specific ultrasonic focus.

  Thus, the one or more ultrasonic transducers are two or more ultrasonic waves at separate frequencies f1, f2,... Intended to form two or more adjacent focal points along the direction of extension of the object of interest. Release the field at the same time. Each of the aforementioned focal points then emits an optical fluorescence signal. This optical fluorescence signal is modulated by the ultrasonic frequency. After detection, analysis of the frequency structure of the detection signal (this analysis can be performed using Fourier transform) can be made to separate each of the aforementioned frequency components individually. By a known or easily derivable relationship between focus location and focus frequency (which can be controlled by choosing the geometry and operating mode of the ultrasonic transducer) at frequencies f1, f2, ... The optical signal components can be attributed to their source location.

  According to an exemplary embodiment, multiple focal points can be applied and a large portion of the field used can be acquired simultaneously. The aforementioned focal points can be arranged in any geometric pattern (eg, adjacent along a line in a cube or square, or spatially separated in a grid). In general, the photodetector does not necessarily have to be spatially resolved. This is because the ultrasonic field is spatially decomposed by the frequency distribution of the emitted ultrasonic waves. However, using an ultrasonic field with spatial resolution, any ultrasonic frequency can be used simultaneously on several focal points farther away than the spatial resolution distance of the photodetector.

  The measurement time acceleration magnification achievable by the present invention depends on the number of simultaneous ultrasonic focal points.

  The present invention allows frequency imaging to be used to parallel optical imaging rather than imaging point by point. The ultrasonic transducer can emit two (or more) ultrasonic fields simultaneously at far ultrasonic frequencies f1 and f2. This can be designed to form two focal points along the axis where the object of interest is located. Each of the aforementioned focal spots then emits an electromagnetic fluorescence signal after absorbing the primary electromagnetic energy. This electromagnetic fluorescence signal is modulated by the ultrasonic frequency. After detection, the above-described frequency component is decomposed by Fourier transform. These can be attributed to the source location.

  It is an advantage of the system according to the invention to achieve a considerable speedup of high resolution optical fluorescence imaging. Due to the frequency-resolved parallelization of imaging processing / scanning of different parts of the object of interest, no signal to noise ratio loss occurs. The invention has application in particular in the fields of molecular imaging, optical imaging of tissue, optical tracking in turbid media, and the like.

  According to exemplary embodiments, the present invention teaches compositions and methods for fluorescence imaging (such as X-ray fluorescence imaging). In this context, the present invention distinguishes between different parts of the particles to be measured in the light measurement spectrum by using two, three or more different frequency values that excite the ultrasound. A parallel measurement system is provided.

  According to one aspect of the invention, the particles used can exhibit contrast agent modulation of the emitted fluorescence by changing the distance between the fluorescent donor and the fluorescent acceptor. By changing the aforementioned distance, the fluorescence can be turned on, modulated, or turned off. For each frequency of the excitation ultrasound, the change in distance can be controlled individually for each part of the object of interest.

  The present invention describes a combined optical ultrasound imaging system in the multi-frequency domain. In this system, ultrasonic waves are used when the spatial resolution is high, and fluorescence detection leads to high sensitivity. By realizing different ultrasonic frequencies, a short measurement time is realized. As a result, moving objects can also be measured without fear of motion artifacts.

  The object of interest can comprise a donor and / or acceptor or donor group and / or acceptor group for energy transfer by FRET.

  Using an ultrasonic field having a plurality of predetermined frequencies, a compound or composition of a specific portion of the object of interest, eg, a flexible vascular particle (eg, It is possible to switch using flexible particles, such as microbubbles with fluorescent donors and / or fluorescent acceptors.

Thus, the particles can be forced to deform or vibrate by an ultrasonic field of a specific frequency (which can be focused). This can result in characteristic time-dependent variations in the distance between the fluorescent donor and the fluorescent acceptor on or within the particle, or on or within the object of interest. According to an exemplary embodiment related to FRET, the energy transfer from a state where there is no energy transfer (effectively 0%) due to the strong dependence of the FRET effect on the distance r (proportional to r ⁻⁶ ). However, the transition to a very effective (effectively 100%) state is very rapid. Thus, it is possible to achieve a large fluorescence modulation and thus a high signal to noise ratio. With the system according to the invention, the spatial resolution can be limited by the size of the ultrasound focus, which can be as low as 1 mm ³ or less. This can be over 1,000 times the resolution of prior art optical X-ray fluorescence tomography. According to the present invention, this high spatial resolution is combined with a high temporal resolution. According to the present invention, fluorescence can be generated by FRET, but can also be generated by other mechanisms of energy transfer such as excited state reactions.

  One exemplary application of the present invention relates to providing an image of a body part or tissue of an individual having a contrast agent that includes particles with fluorescent donors and / or fluorescent acceptors. This can be done by applying ultrasound to the aforementioned body part or tissue and recording the modulation of the fluorescence emitted by the contrast agent.

  The apparatus of the present invention adapted for ultrasound imaging provides an ultrasound multi-frequency source and an apparatus for detecting emitted fluorescence. The light emission can be related to a specific frequency and adjusted locally by focusing the ultrasound beam. It is possible to provide a reconstruction device that realizes a frequency analysis for separating individual contributions by different parts of the target object and generates an image from the detected fluorescence. The control device can control generation of ultrasonic waves and / or recording of ultrasonic waves by emission of light from a light source and / or detection of recorded light. The aforementioned control device can also control the emission of different frequencies of ultrasound emitted to strike different parts of the object of interest.

  Hereinafter, exemplary embodiments according to the present invention will be described.

  Next, an exemplary embodiment of an apparatus for imaging an object of interest will be described. However, the foregoing embodiments are also applicable to arrays and methods for imaging an object of interest, methods of use according to the present invention, program elements and computer readable media.

  The ultrasound device of the device can be adapted to emit at least two different frequencies of ultrasound on at least two separate portions of the object of interest. That is, the ultrasonic transducer can be adapted so that the direction and frequency of a particular mechanical wave packet can be individually adjusted. As a result, it is possible to focus different frequency mechanical waves on different focal points or portions of the object of interest.

  In particular, the ultrasound device can be adapted to emit ultrasound of at least two different frequencies simultaneously (ie in parallel in time) onto at least two separate parts of the object of interest. According to this embodiment, different focal points of the object of interest illuminated by different frequency ultrasounds are illuminated simultaneously. As a result, fluorescent radiation is also emitted virtually simultaneously. However, since the frequency information of the ultrasound is still included in the fluorescence emission, it is possible to distinguish between signals originating from different parts of the object of interest by appropriate frequency analysis of the detection signal.

  The ultrasound device is configured to provide at least two different frequencies on at least two separate portions of the object of interest such that the electromagnetic fluorescent radiation emitted by the at least two separate portions of the object of interest is modulated by at least two different frequencies. And can be adapted to emit ultrasound. That is, by defining the spatial dependence of the frequency of the ultrasonic field, it is possible to adjust the spatial dependence of the frequency of re-emitted electromagnetic radiation. Thus, the modulation frequency of the detection signal contribution makes it possible to retrack the part of the volume of interest (i.e. the voxel of the object of interest) where the detection signal occurred.

  The ultrasound device can be divided into at least two separate ultrasound sources. Each of the at least two separate ultrasound sources can be adapted to emit a particular frequency of ultrasound on the object of interest. Therefore, an array of a plurality of ultrasonic devices can be provided. Separate ultrasonic sources can emit different ultrasonic frequencies and are spaced apart from one another. The geometry of this arrangement defines the focal spot illuminated by the ultrasonic radiation.

  Still referring to the examples described herein, at least two separate ultrasound sources can be arranged linearly and at regular intervals from one another. By spacing between at least two separate ultrasound sources and placing them in a linear order, it is possible to obtain a one-dimensional spectrum from the object of interest. 2D scanning of the object of interest can be done with 1D mechanical movement by moving the linear arrangement of the ultrasound sources along a direction that is approximately perpendicular to the direction of the placement of the separate ultrasound sources It is.

  Alternatively, at least two separate ultrasound sources can be arranged like a matrix and spaced apart from each other. By providing a two-dimensional array of ultrasonic sources, no moving parts are required for scanning, and two-dimensional measurements can be performed in a very short measurement time. For example, separate ultrasound sources can be placed on the nodes of a two-dimensional grid, thus properly defining the focus of the separate ultrasound sources.

  At least two separate ultrasound devices transmit ultrasound at a specific frequency on the object of interest so that the amplitude and phase of the ultrasound emission can be controlled or adjusted separately for each of at least two separate ultrasound sources. Can be adapted for release. The phase (ie vibration state) and amplitude (ie strength or intensity) of the ultrasound can thus be adjusted individually for each ultrasound source.

  The ultrasound device can be implemented as a single ultrasound source adapted to emit at least two different frequencies of ultrasound in separate spatial directions. According to this embodiment, a single multi-frequency ultrasound source or transducer is provided that emits ultrasound in different directions that define different focal points of the ultrasound that strikes the object of interest. This emission of ultrasonic sound towards different parts of the object of interest can occur simultaneously or sequentially.

  The ultrasound device can be adapted to emit ultrasound on an object of interest in one of a group comprising a continuous emitting method, a modulated emitting method, and a pulsed emitting method. . By emitting ultrasound continuously, an intensity detection signal can be achieved, which results in a short measurement time and appropriate statistics. By emitting ultrasound in pulses, the modulation of the emitted fluorescent radiation is also pulsed. As a result, a clear assignment of the excitation ultrasound signal and the emitted detection signal is achieved.

  The electromagnetic radiation detector may be a non-spatial decomposing detector. With the modulation frequency of the detection signal, it is possible to distinguish between the spatial origin of the signal (ie the part of the object of interest where the detection signal was generated), so it has a highly sensitive electromagnetic radiation detector for spatial information There is no need. Thus, it is sufficient for the detector to resolve the frequency and / or intensity information.

  As an alternative to the previous embodiment, the electromagnetic radiation detector may be a spatially resolved detector. At least two of the separate ultrasound sources are separated from each other by a distance such that the electromagnetic fluorescence radiation originating from the different parts that are subjected to the same frequency of ultrasound is spatially distinguished by the electromagnetic radiation detector It can be adapted to emit ultrasonic waves of the same frequency on the part of the object of interest. According to this embodiment, it is possible to apply different parts of the object of interest simultaneously with ultrasound of the same frequency. This is because, according to this embodiment, the electromagnetic radiation detector also has a spatial resolution. Therefore, the object of interest can be divided into segments each having a plurality of portions. Different parts of the segment are emitted by different frequencies of ultrasound. The spatial resolution of the detector can then be approximately equal to the segment dimensions. As a result, the detector can spatially differentiate between radiation from separate segments. Therefore, it is possible to reliably avoid unnecessary interference of the detection signal generated from the portion of the object of interest that has been irradiated with ultrasonic waves having the same frequency.

  The electromagnetic radiation detector can be a frequency-resolved detector (ie, a detector that can distinguish between signals having different frequencies). Furthermore, the detector can time resolve the signal.

  The apparatus can further comprise a reconstruction device adapted to reconstruct an image of the object of interest based on the detected electromagnetic fluorescence radiation. Since the spatial information is encoded into the frequency information, it is possible to reconstruct the geometric information or the structure information from the detection signal.

  The reconstruction device can be particularly adapted to reconstruct an image of the object of interest based on a frequency analysis of detected electromagnetic fluorescence radiation, in particular a Fourier analysis (such as a Fourier transform). The Fourier analysis described above can convert the frequency spectrum into an inverse Fourier space.

  The apparatus can have an electromagnetic radiation source adapted to emit electromagnetic radiation on the object of interest. Instead of using light radiation, it is also possible to use electromagnetic radiation having other wavelengths (such as infrared radiation or ultraviolet radiation). The radiation used depends on the energy required to force the material of the object of interest to emit fluorescent radiation.

  The source of electromagnetic radiation can be adapted to emit electromagnetic radiation on the object of interest in one of a group having a method of emitting continuously, modulated emitting, and emitting in pulses. . The emission method of the electromagnetic radiation source must be synchronized with the emission method of the ultrasonic source. However, providing an electromagnetic radiation source is optional. Alternatively, or additionally, electromagnetic radiation from the environment (eg, sunlight) can be used.

  In the following, an exemplary embodiment of an array for imaging an object of interest will be described. However, the embodiments described above are also applicable to apparatus and methods for imaging an object of interest, methods utilized by the present invention, computer readable media, and program elements.

  The objects of interest in the array can have attached particles having a donor adapted to absorb electromagnetic radiation and / or an acceptor that emits electromagnetic fluorescent radiation. The emission of electromagnetic fluorescence radiation by the particles can be based on a fluorescence resonance energy transfer process (eg, a FRET process).

  According to the present invention, ultrasonically active microbubbles having optically active donors and acceptors can be attached to an object of interest. The donor can absorb the electromagnetic radiation and transfer the absorbed energy to the acceptor so that fluorescent radiation having a frequency different from the excitation electromagnetic radiation is emitted. The efficiency of the energy transfer process, and thus the efficiency of the emission of electromagnetic fluorescent radiation, depends on the distance between the acceptor and the donor. According to the invention, ultrasonic radiation is used as a mechanical pressure wave that adjusts the distance between the acceptor and the donor. Thus, the emitted fluorescent radiation has a frequency contribution of the ultrasonic source.

  According to one embodiment of the present invention, a two-dimensional matrix of transducers can be provided. The amplitude and phase of each transducer can be adjusted individually.

  In order to avoid unnecessary overlapping of the separate focal points, it is possible not to place the separate focal points directly adjacent to each other, but to place them on nodes of a two-dimensional grid or a three-dimensional grid. The distance between adjacent nodes may be greater than the focal spot size.

  The foregoing and further aspects of the invention will be apparent from and will be elucidated with reference to the embodiments described hereinafter.

  The invention will be described in more detail below with reference to exemplary embodiments, but the invention is not limited to such exemplary embodiments.

  In the drawing, it is schematically illustrated. In different drawings, similar or identical components are provided with the same reference signs.

  In the following, referring to FIG. 1A, the principle of fluorescence on compressed vesicle particles according to one embodiment of the present invention will be described.

  FIG. 1A shows a particle 101 in a first state 100 and a second state 120. In the first state 100, particles 101 (eg, vesicles) in a relaxed state are shown. Donor molecule 102 absorbs energy from excitation light 104, but vesicle 101 is in a relaxed state, so donor 102 and acceptor 103 (can emit optical fluorescence radiation when energy is supplied from donor 102). Is too large for efficient energy transfer.

  In contrast, in the second state 120, the compressed or deformed state of the particles 101 is shown. In this specification, energy from the excitation light 104 is transferred from the donor 102 to the acceptor 103 (see the bent arrow 105), and the acceptor 103 emits fluorescence 106.

  According to the present invention, compression of the particles 101 can be achieved by emitting ultrasonic waves on the particles 101 and mechanically vibrating the particles 101 so that a transition between the relaxed state 100 and the compressed state 120 occurs. it can.

  FIG. 1B shows another example of particle 110. That is, the rectangular particle 110 is shown in a relaxed state and two separate excited states.

  Hereinafter, referring to FIG. 2, an imaging arrangement 200 according to an exemplary embodiment of the present invention will be described.

  Particles 211 containing a fluorescent donor and a light acceptor (not shown) are injected into an object of interest 212 (such as a body organ, a human or animal patient body, or any other object to be imaged). The device 200 provides an ultrasound image of the body 212 and a fluorescent image (with a contrast determined by the concentration of the particles 211). In the case of an ultrasound image, the linear ultrasound transducer array 201 transmits several wavelengths of ultrasound pulses similar to those used for normal B-mode imaging.

  The ultrasonic transducer 201 is adapted to emit ultrasonic waves of different frequencies f1 and f2 toward different locations within the object of interest 212. Since the two particles 211 shown in FIG. 2 are arranged at different locations in the object of interest 212, the ultrasonic waves hitting the two particles 211 have different frequencies fl and f2. As the pulse travels toward the object of interest 212, the reflection on the internal surface generates an echo signal that is received by the transducer 201. The ultrasonic receiver 202 moves this echo to a one-dimensional ultrasonic image. The ultrasonic image reconstruction device 203 collects a one-dimensional ultrasonic image and calculates a two-dimensional image therefrom. This can be displayed by the display device 204.

  The fluorescence image is formed in parallel with this as will be described below. As the ultrasonic pulse traverses the object of interest 212, vibration of the particles 211 is effected along that path. Particles 211 that are struck by ultrasound with different frequencies f1 and f2 vibrate accordingly at different frequencies.

  One or more optical excitation sources 207 provide excitation light 231 having a spectral overlap with the absorption spectrum of the donor of particle 211 of object of interest 212.

  The light source 207 may be continuous or in a pulsed state (eg, continuous wave, having a defined (variable) wavelength, modulated state, or pulsed state). The acceptor on the particle 211 subject to vibration generates a fluorescence signal 214 that is proportional to the local concentration of the particle 211 along the path of the pulse and is modulated by the frequency f1 or f2. The fluorescence 214 is detected by a photodiode or photodiode array 208 attached directly to the object of interest 212 to collect as much fluorescence 214 as possible. The diode array 208 can cover as much of the body surface as possible for the same purpose. The light input of the photodiode 208 includes an optical filter that blocks only light having a wavelength defined by the optical excitation source 207 and preferably only passes fluorescence so that background radiation is suppressed to avoid signal interference. be able to.

  The signals detected by the photodiode 208 are summed and the summed signal S (t) can be digitized by an analog / digital converter 209. Since a meaningful signal can only be recorded during the first traversal of the ultrasound pulse after its transmission through the body, the operation of the A / D converter 209 is gated by the ultrasound generator 202. It can be gated by the signal 205. Preferably, the gate signal 205 begins to sample upon transmission of the ultrasonic pulse, and the gate signal 205 is timed until the pulse traverses the entire body 212 and is so pulsed that no useful signal can be recorded anymore. Sampling is stopped after the shorter of the time until decay. The aforementioned time can be calculated from the dimensions of the body 212 and the attenuation depth of the ultrasonic beam. The optical reconstruction device 210 moves the signal S (t) to the one-dimensional fluorescence image.

  In order to improve the resolution in the beam path, the signal can be deconvolved with the pulse shape of the ultrasound pulse supplied by the ultrasound generator 202 on the data connection 206. The optical image reconstruction device 210 collects a one-dimensional optical image and calculates a two-dimensional image therefrom. This can be displayed by the display device 204.

  The optical image reconstruction device 210 performs frequency analysis (particularly, Fourier transform) to distinguish between signals originating from separate particles 211 and modulated by different ultrasonic frequencies f1 or f2. Therefore, the spatial resolution can be reconstructed by knowledge of the frequencies f1 and f2 of the excitation ultrasonic waves.

  The display device 204 can display the ultrasound image and the light image separately or in combination (eg, a color overlay of the light image to the ultrasound image).

  Thus, the imaging array 200 has an ultrasound device 201 adapted to image the object of interest 212 and adapted to emit ultrasound of two different frequencies f1, f2 onto the object of interest 212. The light detector 208 is responsive to absorption of light from the light source 207 and is adapted to detect fluorescence emitted by the object of interest 212 in response to respective ultrasound waves. The ultrasound device 201 is adapted as a multi-frequency ultrasound device, and separates the object 212 of interest such that the electromagnetic fluorescent radiation 214 emitted by the two separate portions 211 of the object of interest 212 has two different frequency contributions. Different ultrasonic waves of f1 and f2 can be emitted toward the two portions 211. The ultrasonic device 201 emits ultrasonic waves on the object of interest 212 so that the amplitude and phase of ultrasonic emission for the two particles 211 can be controlled separately. The ultrasonic device 201 emits ultrasonic waves of two different frequencies f1 and f2 in different spatial directions so as to strike on different particles 211. The electromagnetic radiation detector 208 is a non-spatial decomposing detector. That is, signal contributions originating from separate particles 211 are separated by frequency.

  The optical reconstruction device 210 reconstructs an image of the object of interest 211 based on the detected electromagnetic fluorescence radiation. For this purpose, Fourier analysis of the detected electromagnetic fluorescence radiation is performed by the optical reconstruction device 210. Particles 211 having FRET donors and acceptors can be realized as shown in FIG. 1A or FIG. IB.

  FIG. 3 represents an exemplary embodiment of a data processing apparatus 300 according to the present invention for performing an exemplary embodiment of the method according to the present invention. A data processing device (data processor) 300 shown in FIG. 3 has a central processing unit (CPU) or image processor 301 that is connected to a memory 302 and stores an image representing an object of interest (such as a patient). The data processing device 301 can be connected to multiple input / output networks or diagnostic services (such as a device that images an object of interest). The data processing device 301 can further be connected to a display device 303 (eg, a computer monitor) for displaying image related information calculated or adapted in the data processing device 301. An operator or user can interact with data processor 301 via keyboard 304 and / or other output devices (not shown in FIG. 3). Further, the image processing control processor 301 can be connected to the motion monitor for monitoring the motion of the object of interest via the bus system 305, for example. For example, if the patient's lungs are imaged, the motion sensor may be an expiration sensor. If the heart is imaged, the motion sensor can be an electrocardiogram (ECG).

  Exemplary technical fields in which the present invention can be effectively applied include medical applications, medical tests, and materials science. Improved image quality and reduced computational complexity can be achieved with less effort. The present invention can also be applied in the field of cardiac scanning for detecting heart disease.

  In the following, referring to FIG. 4, an imaging arrangement 400 according to another exemplary embodiment of the invention will be described.

  The imaging array 400 that captures an object of interest includes a first portion 401 at a position x1 along the extension direction 403 and a second portion 402 at a position x2 along the extension direction 403. The device 400 comprises a multi-frequency ultrasound device 404 capable of emitting ultrasound 405 of two different frequencies f1 and f2 on the part 401, 402 of the object of interest. More specifically, the ultrasonic wave 405 having the frequency f 1 is directed to the first portion 401, and the ultrasonic wave 405 having the second frequency f 2 is directed to the second portion 402. Furthermore, the apparatus 400 is responsive to absorption of primary electromagnetic radiation emitted by the electromagnetic radiation source 408 and is responsive to ultrasound 405 to emit electromagnetic fluorescence emitted by the first portion 401 and the second portion 402 of the object of interest. It has an electromagnetic radiation detector 406 that can detect the radiation 407. An electromagnetic radiation source 408 is provided that emits electromagnetic radiation 409 on the first portion 401 and on the second portion 402.

  Although not shown in FIG. 4, the first part 401 and the second part 402 of the object of interest are provided with acceptors and donors as shown in FIG. 1A. Thus, the ultrasound 405 causes deformation / vibration of the aforementioned acceptor and donor-containing particles, thereby resulting in modulation of re-emitted fluorescent emission.

  The electromagnetic radiation from the electromagnetic radiation source 408 is generated at a wavelength such that the electromagnetic radiation 409 can be absorbed in a particular compressed state of the particles adhering to the first portion 401 and the second portion 402. If the compressed state provided by the ultrasound 405 in the first portion 401 or the second portion 402 is sufficiently small in distance between the donor and the acceptor (ie, in a particular mechanical vibration phase state), the donor to acceptor Energy transfer to is possible. This causes the acceptor to re-emit the fluorescent radiation 407. This fluorescent radiation 407 carries the fingerprint of that frequency f1 or f2 of the ultrasonic wave 405 hitting a particular one of the parts 401 and 402. Therefore, the detection signal detected by the electromagnetic radiation detector 406 has a characteristic frequency contribution corresponding to the ultrasonic frequencies f1 and f2. As a result, the spatial distribution of the portions 401 and 402 of the object of interest can be reconstructed by Fourier analysis of the detected spectrum.

  As shown in FIG. 4, the ultrasonic device 404 is adapted to emit ultrasonic waves of two different frequencies f1, f2 on two separate portions 401 in parallel (ie, simultaneously). Since the mechanical frequency at which the particles of the parts 401, 402 oscillate varies in response to the excitation ultrasound, the fluorescent radiation has a separate frequency contribution.

  The ultrasound device 404 is a single ultrasound adapted to emit ultrasound of two different frequencies f1, f2 in different spatial directions so that it hits a particular part of the parts 401, 402 at positions xl and x2. Realized as a sound wave source.

  A reconstruction device 410 coupled to the output of the electromagnetic radiation detector 406 reconstructs an image of the object of interest (ie, the location of the portions 401, 402) based on the Fourier transform of the detected electromagnetic fluorescence radiation. The aforementioned data is provided to the display device 411 that displays the reconstructed image.

  Thus, FIG. 4 shows the principle of using frequency coding to parallelize optical imaging rather than imaging point by point. The ultrasonic transducer 404 emits two ultrasonic fields simultaneously at separate frequencies f1 and f2 intended to form two adjacent focal points along the axis 403. Each of the aforementioned focal points then emits an optical fluorescence signal 407 that is modulated by the ultrasonic frequency f1 or f2. After light detection by the electromagnetic radiation detector 406, the Fourier transform performed in the reconstruction device 410 decomposes the frequency components that can be attributed to the source locations xl and x2, as shown in FIG.

  FIG. 5 is a diagram 500 having an abscissa 501 where the modulation frequency f is shown. Along the ordinate 502 is shown the intensity of the optical signal (proportional to the amount of material provided to particles at a particular position x along axis 403). Therefore, the shape of the detection signal shown in FIG. 5 is a mapping of the material distribution along the x-axis 403. The intensity along the ordinate 502 is a mapping in the z direction 412 shown in FIG.

  In the following, referring to FIG. 6, an imaging arrangement 600 according to another exemplary embodiment of the invention will be described.

  The object of interest 212 to be imaged is placed on the mounting table 601. The object of interest 212 is (virtually) divided into first to seventh parts (602 to 608). An ultrasonic transducer 609 is provided that generates ultrasonic waves 405 that strike separate portions 602-608 of the object of interest 212. Each portion 602 to 608 is illuminated with a specific frequency f1 to f7 of ultrasonic waves (each generated by a specific one of the first to seventh transducer sources 611 to 617).

  The electromagnetic radiation source 409 generates a substantially monochrome excitation radiation 409 that hits all portions 602-608. All parts 602 to 608 of the object of interest 212 are provided with donors and acceptors at a certain distance from each other. This distance is modulated by mechanical vibrations generated by the first through seventh transducer sources 611-617. As a result, in certain compressed states of mechanically oscillating particles, the distance between the donor and acceptor allows fluorescence 404 to be generated by energy transfer from the absorbing electromagnetic radiation 409 absorbed by the donor to the acceptor. Small enough to make. In another particular compression state of the mechanically oscillating particle, the distance between the donor and the acceptor is too large to allow energy transfer from the absorbing electromagnetic radiation 409 absorbed by the donor to the acceptor, and thus In this state, the fluorescence 407 is not generated.

  The generated fluorescence 407 is detected by an electromagnetic radiation detector 610 that decomposes in a non-spatial manner. However, the fluorescence signals of the different parts 601 to 608 can be separated by different modulation frequencies fl to f7. In the reconstruction device 410, Fourier analysis is performed to separate the separate frequency contributions and reconstruct the image displayed on the display device 411.

  Hereinafter, referring to FIG. 7, an imaging arrangement 700 according to another embodiment of the present invention will be described.

  The imaging array 700 is imaged in that an ultrasound transducer 701 (see FIG. 7) is provided that has six separate ultrasound sources that are linearly arranged and adapted to emit ultrasound having a frequency f1 or f2. Different from array 600. The object of interest 212 is (virtually) divided into six parts 602-607. Here, the first portion 602 and the second portion 603 form a first segment 702, the third portion 604 and the fourth portion 605 form a second segment 703, and a fifth portion 606. And the sixth portion 607 forms a third segment 704. Separate portions of a segment within a single segment are illuminated by ultrasound having different frequencies. However, different portions of different segments can be illuminated with the same ultrasonic frequency.

  According to the embodiment shown in FIG. 7, the detector 708 is implemented as a spatially resolved electromagnetic radiation detector 708 that can distinguish between the fluorescent radiation 704 resulting from the three segments 702-704. More particularly, the fluorescence radiation 704 resulting from the first segment 702 is geometrically detected by the first detector portion 705 and the radiation from the second segment 703 is geometrically detected by the second detector portion 706. Detected and the radiation originating from the third portion 704 is detected by the third detector portion 707. The output of the detector 708 is supplied to the reconstruction device 410. Here, the result to be reproduced is displayed on the display device 411.

  Within a particular segment 702-704, separate portions 602-607 of the object of interest 212 are illuminated by ultrasound having different frequencies. However, according to the spatial resolution of the detector 708, it is possible to use only two ultrasonic frequencies f1, f2.

  In the following, exemplary embodiments of particles having a donor and an acceptor are described.

  The donor or acceptor may be any molecule, group of molecules and complex of the donor and acceptor types and examples represented in the present invention.

  The particles can be deformable or flexible. The particles can be spherical particles such as vesicles. “Vesicle” refers to an entity generally having one or more walls or membranes that form one or more internal cavities. Vesicles can be formulated with stabilizing materials such as lipids, proteins, polymers, surfactants and / or carbohydrates. The lipids, proteins, polymers, surfactants and / or other vesicles that make up the stabilizing material can be natural, synthetic or semi-synthetic. The wall or membrane may be concentric or another shape. The stabilizing compound can be in the form of one or more monolayers or bilayers. In the case of two or more monolayers or bilayers, the monolayer or bilayer can be concentric. The stabilizing compound can be a monolayer vesicle (having one monolayer or bilayer), a small layer vesicle (having about 2 or about 3 monolayers or bilayers), or a multilayer vesicle ( About 4 or more monolayers or bilayers). The wall or membrane of the vesicle may be substantially filled (uniform), porous or semi-porous. Voids inside the vesicle can be, for example, water, oil, fluorinated oil, gas, gaseous precursors, liquids, fluorinated liquids (if necessary), and / or various liquids including other materials Can be filled with gaseous or solid materials (or combinations thereof). Vesicles can also have photoactive agents, bioactive agents or drug compounds and / or targeting ligands.

  Spherical particles, which are suitable particles for the compounds and methods of the present invention, are preferably biocompatible and / or highly compressible or consumable. An example is microbubbles. This can be a gas-filled small 3-5 μm diameter sphere that, when exposed to an ultrasonic pressure field, provides enhancement by several mechanisms related to its high compressibility (De Jong, N et al. See Ultrasonics, 1996, 34 (2-5) (pp. 587-590), Moran, CM et al., Ultrasound in Medicine & Biology, 2002, 28 (6), pp. 785-791). Available ultrasound contrast agents are sold, for example, by the company Bristol-Myers-Squibb, which has a lipid shell and a sphere of 1.1 to 3.3 microns diameter with an interior of octafluoropropane gas, There is a Definity (TM) developed by Unger of ImaRX. Optison ™, sold by Amersham and originally developed by Mallinckrodt, has a 2 to 4.5 micron diameter sphere with an albumin shell and containing octafluoropropane gas including. Albnex ™, also sold by Amersham, is a first generation drug that is similar to Optison ™ but contains air. Sonobue (TM) sold by Bracco is a phospholipid-coated sulfur hexafluoride microbubble having an average size of 2.5 microns. Echovist (TM) and Levovist (TM), sold by Schering, have been in use for some time now and are sugar stabilizing with a less controlled size distribution (greater than 5 μm) Has atmospheric microbubbles.

  The physical mechanism of ultrasound contrast involves the high compressibility of the gas in the bubble and the physical dimensions of the bubble (de Jong (see above), Advanced in Ultrasound, Clinical Radiology, 2002, 57 ( 3), pp. 157-177, Ultrasound contrast agents by Callida, F et al .: Basic principles, European Journal of Radiology, 1998, 27 (2), pp. 157-160). At diagnostic imaging frequencies, microbubbles can experience vibrations that are many multiples of the static diameter. This effect is particularly great near bubble resonance. By careful selection of the elastic properties of the gas and shell material within the microbubble, the stability of the bubble and this contrast effect can be manipulated.

Liposomes are also potentially useful contrast agents for ultrasound imaging. Liposomes have been used for over 25 years as a potential mechanism for drug administration. Most liposomes have mainly fat and are not echogenic. Liposomes usually have acoustically reflective non-gaseous multilayer lipids (Demos, S et al., Journal of the American College of Cardiology, 1999, 33: pp. 867-875). The aforementioned liposomes are characterized by the presence of many small, irregularly shaped vesicles arranged in a “raspberry-like” appearance. Liposomes are usually smaller than 1 micron in diameter. By using liposomes, the scattering process provides an enhanced appearance in ultrasound imaging. However, liposomes have low stability and half-life, and there is no major mechanical resonance associated with liposomes. According to another embodiment of the invention, the particles are micellar. A micelle represents a colloidal entity formulated by lipids. In exemplary embodiments, the micelles have a single, double, or hexagonal H II phase structure (see US Pat. No. 6,033,645).

  Particles having a shape different from the spherical shape can be deformed by ultrasonic waves in order to change the distance between the fluorescent donor molecule and the fluorescent acceptor molecule existing in the particle shape. Non-spherical particles suitable for the compounds and methods of the present invention are rod-like or Y-shaped, tubular, or rectangular.

  According to another embodiment of the invention, the particles are aerogels. Airgel represents a generally spherical or spheroid entity characterized by a plurality of small, internal cavities (see US Pat. No. 6,106,474). Aerogels can be formulated with synthetic materials (eg, foams prepared by baking resorcinol and formaldehyde) and natural materials (such as carbohydrates (polysaccharides) and proteins).

  According to another embodiment of the invention, the particles are inclusion compounds. Inclusion compounds represent packed, semi-porous or porous particles that can be associated with vesicles. In an exemplary form, the inclusion compound may constitute a cage-like structure that optionally includes a cavity having one or more vesicles bound to the inclusion compound. A stabilizing material can be combined with the inclusion compound to facilitate the association between the inclusion compound and the vesicles, if desired. Inclusion compounds can be formulated, for example, with porous apatite (such as calcium hydroxyapatite) and polymer and metal ion precipitates (such as alginic acid precipitated with calcium salts) (US Pat. No. 5,086,620). Refer to the book).

  According to the method of the present invention, the particles are exposed to an ultrasonic field, which results in deformation and / or vibration of the particles. Ultrasound is a longitudinal compression wave. In the case of a longitudinal wave, the displacement of the particles in the medium is parallel to the direction of the wave for a moving wave whose displacement is perpendicular to the direction of propagation. Ultrasound in particular represents any frequency at the high end or above the audible spectrum of the human ear (20 Hz to 20 kHz). Medical imaging typically uses a frequency of about 2.5 MHz. According to the present invention, depending on the type of tissue being examined in the type of particle being used, it is possible to select lower or higher frequencies as required. A parameter commonly used in ultrasound imaging is the mechanical index (= refracted pressure or negative pressure of the peak divided by the square root of the ultrasound frequency). The mechanical index is related to the negative pressure of the peak in the tissue, and thus the stiffness of the particles that can be used and still provide sufficient deformation to achieve the effects used in the embodiments of the present invention. Involved. The clinical value of MI is 1 or more and 2 or less. In certain embodiments, the spherical particles of the present invention are capable of compressing volume by a factor of at least 5, greater than about 10, 25, 50, or 100 to attract the fluorescent donor and acceptor molecules together. is there. In another specific example, the spherical particles of the present invention can expand in volume by a factor of at least 5 or more, about 10, 25, 50 or 100 or less to keep the donor and acceptor molecules away from each other. It is.

  According to one embodiment of the present invention, fluorescent donors and fluorescent acceptors on the particles of the present invention can exchange energy by FRET (Fluorescence Resonance Energy Transfer). FRET is the transfer of excited state energy from donor to acceptor and can occur when the emission spectrum of the donor fluorophore overlaps the absorption spectrum of the acceptor fluorophore. Thus, only the donor and acceptor molecules that are bound and within a specific distance can be monitored by exciting at the donor's absorption maximum and monitoring the emission of the acceptor fluorophore on the long wavelength side. Is possible.

  Examples of useful donor-acceptor pairs include NBD (ie, N (7-nitrobenz-2-oxa-1,3-diazol-4-yl))-rhodamine, NBD-fluorescein-eosin or erythrosine, dansyl- Contains rhodamine and acridine orange-rhodamine. Examples of suitable commercial labels that can represent FRET include fluorescein-tetramethylrhodamine, 4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacene-3-propion Acid, succinimidyl ester (commercially available under the trade name BODIPY FL from Molecular Probes, Eugene, Oregon) -4,4-difluoro-5-phenyl-4-bora-3a, 4a-diaza- s-Indacene-3-propionic acid, succinimidyl ester (eg, commercially available under the name BODIPY R6G from Molecular Probes, Eugene, OR), Cy3.5 monofunctional NHS-ester-Cy5 .5 monofunctional NHS-ester, Cy3 monofunctional NHS-ester-Cy5 monofunctional NHS-ester, and Cy5 monofunctional NHS-ester-Cy7 monofunctional NHS-ester (all Amersham Biosciences (England, Available on the market from Buckinghamshire In a), and, carboxylic acids ALEXA FLUOR 647, succinimidyl ester - acid ALEXA FLUOR 647, succinimidyl ester (all from Molecular Probes, Inc., are available on the market) are included.

  Other examples of molecules used in FRET include fluorescein derivatives (5-carboxyfluorescein (5-FAM), 6-carboxyfluorescein (6-FAM), fluorescein-5-isothiocyanate (FITC), 2'7 ' -Dimethoxy-4'5'-difluoro-6-carboxyfluorescein (JOE), etc.), rhodamine derivatives (N, N, N ', N'-tetramethyl 6-carboxyrhodamine (TAMRA), 6-carboxy · X-rhodamine (R6G)), tetramethyl-indocarbocyanine (Cy3), tetramethyl-benzindocarbocyanine (Cy3.5), tetramethyl-indodicarbocyanine (Cy5), tetramethyl-indodicarbocyanine (Cy7) , 6-carboxy-X-rhodamine (ROX), hexachlorofluorescein (HEX), tetrachlorofluorescein TET, R-phycoerythrin, 4- (4'-dimethylaminophenyla Zo) benzoic acid (DABCYL) and 5- (2′-aminoethyl) aminonaphthalene-1-sulfonic acid (EDANS).

  Further FRET donor and acceptor molecules suitable for the methods of the invention include fluorescent proteins such as DS Red, GFP (green fluorescent protein) or variants thereof, EYFP (enhanced yellow fluorescent protein), ECFP ( Enhanced cyan fluorescent protein), EBFP (enhanced blue fluorescent protein).

  The fluorescent donor and acceptor pair of FRET can be localized outside or inside the particle, or can be embedded in the particle film or particle shell. In certain embodiments, the donor is inside the particle while the acceptor is outside the particle or within the particle wall. Fluorescent donor and acceptor pairs that exchange energy by FRET can be covalently bound to the particle, or can be reversibly bound to the particle by ionic interactions or hydrophilic bonds. In certain embodiments, the donor and acceptor are inside or outside the particle. Due to the aforementioned bubble compression and expansion, the donor and acceptor are either drawn close to each other or pulled apart from each other.

  In certain embodiments, the fluorescent donor molecule and the fluorescent acceptor molecule are covalently attached to the ultrasound particle or to the compound used to make the compound. In another embodiment, the fluorescent donor and acceptor are not on the ultrasound particle. For example, donor molecules and / or acceptor molecules can be injected after a bubble occupies the die in the tissue. It is also possible to inject a quencher or the like. All of the aforementioned chemicals can react with the tissue to become active or inactive.

  In another example, the fluorescent acceptor and / or fluorescent donor binds weakly to the ultrasound particles.

  In certain embodiments, the particle is a compound or agent that targets the complete particle to a tissue or cell type, eg, by a tissue or cell specific bioagent (eg, a monoclonal or polyclonal antibody). And further compounds or agents. An example of this is a particle with antibodies against bacteria or viruses, thereby enabling sensitive and specific detection of infection using ultrasound.

  The term “comprisng” does not exclude other components or steps, and “a” and “an” do not exclude a plurality. Also, the components described in connection with different embodiments can be combined.

Reference signs in the claims should not be construed as limiting the scope of the claims.
Reference code list:
100 First state
101 spherical particles
102 Donor
103 Acceptor
104 excitation light
105 Curved Arrow
106 Acceptor fluorescence
120 Second state
130 rectangular particles
200 imaging array
201 ultrasonic transducer
202 ultrasonic generator
203 Image reconstruction device
204 Display device
205 Gating signal
206 Ultrasonic envelope signal
207 Photoexcitation source
208 Fluorescence detector
209 Analog / digital converter
210 Optical reconstructor
211 FRET donor and acceptor particles
212 Object of interest
213 photoexcitation light
214 fluorescence
300 data processor
301 Central processing unit
302 memory
303 Display device
304 keyboard
305 bus system
400 imaging array
401 1st part
402 Second part
403 Extension direction
404 Multi-frequency ultrasound system
405 ultrasound
406 Electromagnetic radiation detector
407 Electromagnetic fluorescence radiation
408 Electromagnetic radiation source
409 Electromagnetic radiation
410 reconstruction equipment
411 Display device
412 z direction
500 Figure
501 abscissa
502 ordinate
600 imaging array
601 mounting table
602 first part
603 second part
604 third part
605 Fourth part
606 5th part
607 sixth part
608 7th part
609 Ultrasonic transducer
610 Non-spatial decomposing electromagnetic radiation detector
611 First transducer source
612 Second transducer source
613 Third transducer source
614 Fourth transducer source
615 fifth transducer source
616 Sixth transducer source
617 Seventh Transducer Source
700 imaging array
701 Ultrasonic transducer
702 1st segment
703 2nd segment
704 Third segment
705 First detector part
706 Second detector part
707 Third detector part
708 Spatially resolved electromagnetic radiation detector

FIG. 4 illustrates the principle of fluorescence on a compressed spherical vesicle particle, according to an illustrative embodiment of the invention. FIG. 5 is a diagram showing another embodiment in which particles have a rectangular shape or a shape similar to a bar. FIG. 3 shows an arrangement for imaging an object of interest, according to an illustrative embodiment of the invention. 1 is a schematic block diagram of a computer system that controls an imaging device that combines ultrasound imaging and fluorescence imaging, in accordance with an embodiment of the present invention. FIG. 4 is a schematic diagram of an array for imaging an object of interest, according to another exemplary embodiment of the present invention. FIG. 5 is a diagram showing reconstruction of an image of an object of interest using the arrangement shown in FIG. FIG. 6 shows an arrangement for imaging an object of interest according to another embodiment of the invention. FIG. 6 shows an arrangement for imaging an object of interest according to yet another embodiment of the invention.

Claims (28)

An apparatus for imaging an object of interest, the apparatus comprising an ultrasound device and an electromagnetic radiation detector,
The ultrasound device is adapted to simultaneously emit at least two different frequencies of ultrasound onto the object of interest;
The electromagnetic radiation detector is responsive to absorption of primary electromagnetic radiation and adapted to detect electromagnetic fluorescent radiation emitted by the object of interest in response to the ultrasound;
The ultrasound device emits ultrasound of at least two different frequencies on at least two separate portions of the object of interest such that the at least two separate portions of the object of interest are emitted simultaneously; and A device adapted to emit simultaneously the electromagnetic fluorescence radiation emitted by the at least two separate parts of the object of interest such that it is modulated by the at least two different frequencies.   The apparatus of claim 1, wherein the ultrasound apparatus is adapted to emit at least two different frequency ultrasound waves on at least two separate portions of the object of interest.   The apparatus of claim 1, wherein the ultrasound apparatus is adapted to emit at least two different frequency ultrasounds simultaneously on at least two separate portions of the object of interest.   2. The apparatus of claim 1, wherein the ultrasound device transmits at least two different frequency ultrasounds on at least two separate portions of the object of interest, and adjacent portions of the portions have a predetermined distance. A device that is only spaced apart and adapted to emit so that the area between adjacent parts is not subject to ultrasonic irradiation.   5. The apparatus of claim 4, wherein the ultrasound device emits ultrasound so that the at least two separate portions irradiated by ultrasound are arranged to form a two-dimensional lattice or a three-dimensional lattice. A device adapted to do.   The apparatus of claim 1, wherein the ultrasound device is divided into at least two separate ultrasound sources, each of the at least two separate ultrasound sources transmitting ultrasound of a specific frequency on the object of interest. A device adapted to discharge into.   The apparatus of claim 6, wherein the at least two separate ultrasound sources are arranged linearly.   The apparatus of claim 6, wherein the at least two separate ultrasound sources are arranged like a matrix.   7. The apparatus of claim 6, wherein the at least two separate ultrasound sources are such that the amplitude and phase of the emission of ultrasound can be adjusted separately for each of the at least two separate ultrasound sources. A device adapted to emit ultrasound of a specific frequency.   The apparatus of claim 1, wherein the ultrasound apparatus is implemented as a single ultrasound source adapted to emit at least two different frequencies of ultrasound in different spatial directions.   2. The apparatus of claim 1, wherein the ultrasound device is on the object of interest in one of a group having a continuously emitting manner, a modulated emitting manner, and a pulse emitting manner. A device adapted to emit ultrasound.   The apparatus of claim 1, wherein the electromagnetic radiation detector is a non-spatial decomposing detector.   7. The apparatus of claim 6, wherein the electromagnetic radiation detector is a spatially resolved detector, and at least two of the separate ultrasonic sources are electromagnetic waves originating from separate portions that are subjected to ultrasonic waves of the same frequency. An apparatus adapted to emit ultrasonic waves of the same frequency on portions of the object of interest that are separated from each other by a distance such that fluorescent radiation is spatially distinguished by the electromagnetic radiation detector.   The apparatus of claim 1, wherein the electromagnetic radiation detector is a frequency-resolved detector.   The apparatus of claim 1, comprising a reconstruction device adapted to reconstruct an image of the object of interest based on the detected electromagnetic fluorescence radiation.   16. The apparatus according to claim 15, wherein the reconstruction device is adapted to reconstruct an image of the object of interest based on a frequency analysis of the detected electromagnetic fluorescence radiation.   16. The apparatus of claim 15, wherein the reconstruction device is adapted to reconstruct an image of the object of interest based on a Fourier analysis of the detected electromagnetic fluorescence radiation.   The apparatus of claim 1, comprising an electromagnetic radiation source adapted to emit the primary electromagnetic radiation onto the object of interest.   The apparatus of claim 18, wherein the electromagnetic radiation source is adapted to emit substantially monochrome electromagnetic radiation onto the object of interest.   The apparatus of claim 18, wherein the electromagnetic radiation source is adapted to emit optical light onto the object of interest.   19. The apparatus of claim 18, wherein the source of electromagnetic radiation emits the electromagnetic radiation in a manner of a group having a continuous emitting manner, a modulated emitting manner, and a pulse emitting manner. A device adapted to release on top. A device array for imaging an object,
The object;
A device arrangement comprising the device of claim 1 for imaging the object.   23. A device arrangement according to claim 22, wherein the object is attached with particles having a donor adapted to absorb electromagnetic radiation and / or an acceptor emitting electromagnetic fluorescent radiation.   24. A device arrangement according to claim 23, wherein the emission of electromagnetic fluorescent radiation by the particles is based on a fluorescence resonance energy transfer process. A method for imaging an object of interest, comprising:
Emitting ultrasonic waves of at least two different frequencies onto the object of interest;
Detecting electromagnetic fluorescence radiation emitted by the object in response to absorption of primary electromagnetic radiation and in response to the ultrasound.   The apparatus according to claim 1, wherein the object is imaged of a particle that has a donor that can be attached to the object of interest and is adapted to absorb electromagnetic radiation and / or an acceptor that emits electromagnetic fluorescent radiation, or 23. A method for use with the device arrangement of claim 22. A computer readable medium having stored thereon a computer program for imaging an object of interest, said computer program being executed by a processor,
Emitting ultrasonic waves of at least two different frequencies onto the object of interest;
A computer readable medium responsive to absorption of primary electromagnetic radiation and detecting electromagnetic fluorescent radiation emitted by the object of interest in response to the ultrasound. A program for imaging an object of interest,
When executed by the processor,
Emitting ultrasonic waves of at least two different frequencies onto the object of interest;
A program adapted to respond to absorption of primary electromagnetic radiation and to detect electromagnetic fluorescent radiation emitted by the object of interest in response to the ultrasound.

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